Loss of Thermogenic Energy Expenditure via Targeted Deletion of Transferrin Receptor 1 in Adipocytes Instigates Hepatic Steatosis and Insulin Resistance

Abstract Objectives Adipocytes are critical for keeping the whole-body energy balance by depositing energy into TG, secreting fatty acids, and burning energy into heat. We recently reported that iron metabolism in adipose tissue is regulated in a depot-specific manner, and plays an important role in thermogenesis. However, it is poorly understood whether adipocyte iron status alters systemic energy balance. This study aimed to investigate the metabolic impact of the adipocyte-specific deletion of transferrin receptor 1 (Tfr1), the single most critical iron transporter. Methods Adipocyte-specific Tfr1 knockout mice (ASKO) were generated by crossing the adiponectin-Cre transgenic mice with the Tfr1-floxed mice. The metabolic phenotypes of ASKO mice were characterized in basal level and high fat (HF)-fed status. The insulin sensitivity was assessed by glucose (GTT) and insulin tolerance test (ITT). To evaluate the thermogenic capacity, the mice were employed to the heat/cold cycle (31°C for 14 days to normalize the baseline, followed by at 4°C for 7 days). Results In the basal level, the targeted deletion of adipocyte Tfr1 resulted in the reductions in fat mass (p < 0.05) and the iron content (p < 0.01) both in the WAT and BAT, and the impairment of BAT development, including bleached color. ASKO displayed diminished thermogenic function (p < 0.05), but no overt metabolic adaptation was examined compared to the wildtype littermates. However, the HF-diet challenge instigated the glucose intolerance (p < 0.01), insulin resistance (p < 0.01), and hepatic TG content (p < 0.01) in the ASKO mice compared to wildtype without differences in body weight. Furthermore, the heat/cold cycle treatment in the ASKO caused 1) abolished beige fat formation, 2) augmented immune cell infiltration in WAT, 3) enlarged liver due to massive TG accumulation, and 4) elevated serum NEFA and cholesterol levels. Conclusions Dysregulation of adipocyte iron metabolism by deletion of Tfr1 significantly destroys the thermogenic capacity, leading to hepatic steatosis, insulin resistance, and dyslipidemia. Our works have revealed the metabolic contribution of adipose iron homeostasis to maintain systemic energy balance via thermogenic energy expenditure. Funding Sources National Institutes of Health Grant 1R21HD094273

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Maternal adiposity and energy balance after normotensive and preeclamptic pregnancies

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab223 ◽

2021 ◽

Author(s):

Sarah L McLennan ◽

Amanda Henry ◽

Lynne M Roberts ◽

Sai S Siritharan ◽

Melissa Ojurovic ◽

...

Keyword(s):

Insulin Resistance ◽

Body Composition ◽

Energy Balance ◽

Energy Expenditure ◽

Energy Intake ◽

Postpartum Period ◽

Food Diary ◽

Lifestyle Behaviour ◽

Cross Sectional

Abstract Background Preeclampsia is a major pregnancy complication associated with long-term maternal cardiometabolic disease. Research generally is focused on metabolic and pathophysiological changes during pregnancy, however, there is much less focus on the early postpartum period in subjects who suffered preeclampsia. The aim of this study was to (a) characterise energy intake and expenditure six months following normotensive and preeclamptic pregnancies, and (b) examine associations between energy balance, body composition, insulin resistance measures (HOMA-IR), and clinical characteristics. Design A cross-sectional study six months following normotensive (n=75) and preeclamptic (n=22) pregnancies was performed. Metabolic measurements included: anthropometrics measures, body composition via bioelectrical impedance analysis, 24-hour energy expenditure via SenseWear Armbands, energy intake via a three-day food diary, and serum metabolic parameters. Results Six months following preeclampsia, women had a significantly higher weight (77.3±20.9kg versus 64.5±11.4kg, p=0.01), fat mass percentage (FM%) (40.7±7.4% versus 34.9±8.1%, p=0.004), and insulin resistance (HOMA-IR 2.2±1.5 versus 1.0±0.7, p=0.003), as well as reduced HDL levels (1.5±0.4 mmol/L versus 1.8±0.4 mmol/L, p=0.01) compared to normotensive women. Women post-preeclampsia had lower activity-related energy expenditure (p=0.02) but a decreased total energy intake (p=0.02), leading to a more negative energy balance compared to their normotensive counterparts (-1,942 kJ/24-hours versus -480 kJ/24-hours; p=0.02). Conclusion Increases in insulin resistance and FM%, reduced HDL, and more sedentary lifestyles characterise the postpartum period following preeclamptic compared with normotensive pregnancies. Early post-preeclampsia interventions, such as lifestyle behaviour change, should be implemented and assessed to determine whether they reduce long-term cardiometabolic risk in women who experienced preeclampsia during pregnancy.

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Transferrin Receptor 1-Associated Iron Accumulation and Oxidative Stress Provides a Way for Grass Carp to Fight against Reovirus Infection

International Journal of Molecular Sciences ◽

10.3390/ijms20235857 ◽

2019 ◽

Vol 20 (23) ◽

pp. 5857 ◽

Cited By ~ 1

Author(s):

Quanyuan Wan ◽

Zhiwei Liao ◽

Youliang Rao ◽

Chunrong Yang ◽

Jianfei Ji ◽

...

Keyword(s):

Oxidative Stress ◽

Virus Infection ◽

Iron Metabolism ◽

Transferrin Receptor ◽

Grass Carp ◽

Essential Element ◽

Host Cells ◽

Ctenopharyngodon Idella ◽

Feed Additive ◽

Transferrin Receptor 1

Iron is an essential element, closely linked with host immune responses. Nevertheless, the relationship between iron metabolism and virus infection is still unclear in aquatic vertebrates. To address this issue, we employed grass carp (Ctenopharyngodon idella) and its lethal virus, grass carp reovirus (GCRV), a double-strand RNA virus, as models. Our results demonstrate that GCRV infection increases the iron content and alters the expression of iron metabolism-related genes both in vivo and in vitro. Of note, the expression of C. idella transferrin receptor 1 (CiTfR1) rather than transferrin is upregulated upon GCRV infection. To clarify the implications of CiTfR1 upregulation for antiviral immunity, we proved that CiTfR1 was not a helper for GCRV invasion, but instead, it inhibited GCRV infection and promoted cell proliferation by facilitating the accumulation of intracellular labile iron pool (LIP), which increases intracellular oxidative stress. Interestingly, we found that CiTfR1 overexpression inhibited the mRNA expression of C. idella interferon 1 (CiIFN1) and CiIFN3. The present study reveals a novel antiviral defense mechanism in teleost where TfR1 induces the accumulation of LIP, leading to the suppression of virus infection and the proliferation of host cells, indicating that iron can be used as a medicated feed additive for the control of animal viral disease.

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Insulin resistance influences iron metabolism and hepatic steatosis in type II diabetes

Gastroenterology ◽

10.1016/s0016-5085(00)70193-4 ◽

2000 ◽

Vol 118 (5) ◽

pp. 986-987 ◽

Cited By ~ 22

Author(s):

Mauro Viganò ◽

Anna Vergani ◽

Paola Trombini ◽

Massimo Pozzi ◽

Felice Paleari ◽

...

Keyword(s):

Insulin Resistance ◽

Hepatic Steatosis ◽

Iron Metabolism ◽

Type Ii Diabetes ◽

Type Ii

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Brown Adipose Tissue: A New Target for Antiobesity Therapy

The Indonesian Biomedical Journal ◽

10.18585/inabj.v2i2.115 ◽

2010 ◽

Vol 2 (2) ◽

pp. 4

Author(s):

Anna Meiliana ◽

Andi Wijaya

Keyword(s):

Adipose Tissue ◽

Energy Balance ◽

Energy Expenditure ◽

Brown Adipose Tissue ◽

Positive Energy ◽

The Past ◽

Obesity And Diabetes ◽

Brown Adipose ◽

Adult Humans ◽

Thermogenic Capacity

BACKGROUND: Human fat consist of white and brown adipose tissue (WAT and BAT). Though most fat is energy-storing WAT, the thermogenic capacity of even small amounts of BAT makes it an attractive therapeutic target for inducing weight loss through energy expenditure.CONTENT: Over the past year, several independent research teams used a combination of positron-emission tomography and computed tomography (PET/CT) imaging, immunohistochemistry and gene and protein expression assays to prove conclusively that adult humans have functional BAT. BAT is important for thermogenesis and energy balance in small mammals and its induction in mice promotes energy expenditure, reduces adiposity and protects mice from diet-induced obesity. The thermogenic capacity of BAT is impressive. In humans, it has been estimated that as little as 50g of BAT could utilize up to 20% of basal caloric needs if maximally stimulated.SUMMARY: The obesity pandemic requires new and novel treatments. The past few years have witnessed multiple studies conclusively showing that adult humans have functional BAT, a tissue that has a tremendous capacity for obesity-reducing thermogenesis. Novel therapies targeting BAT thermogenesis may be available in the near future as therapeutic options for obesity and diabetes. Thermogenic ingredients may be considered as functional agents that could help in preventing a positive energy balance and obesity.KEYWORDS: brown adipose tissue, thermogenesis, energy expenditure, antiobesity therapy

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Rhein ameliorates fatty liver disease through negative energy balance, hepatic lipogenic regulation, and immunomodulation in diet-induced obese mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00332.2010 ◽

2011 ◽

Vol 300 (5) ◽

pp. E886-E893 ◽

Cited By ~ 53

Author(s):

Xiaoyan Sheng ◽

Min Wang ◽

Meng Lu ◽

Beili Xi ◽

Hongguang Sheng ◽

...

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Liver Disease ◽

Energy Balance ◽

Fatty Liver ◽

Hepatic Steatosis ◽

Fatty Liver Disease ◽

Binding Protein ◽

Negative Energy ◽

Negative Energy Balance

Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, and inflammatory disorders. In this study, we tested the effect of rhein, a lipophilic anthraquinone derived from a traditional Chinese herbal medicine Rheum palmatum L., on NAFLD-associated hepatic steatosis, insulin resistance, and the T helper (Th)1/Th2 cytokine imbalance in high-fat diet-induced obese (DIO) mice. We found that oral administration of rhein for 40 days significantly increased energy expenditure, reduced body weight, particularly body fat content, improved insulin resistance, and lowered circulating cholesterol levels in DIO mice without affecting food intake. Rhein treatment also reduced liver triglyceride levels, reversed hepatic steatosis, and normalized alanine aminotransferase (ALT) levels in these mice. Gene analysis and Western blot showed that rhein markedly suppressed the expression of the lipogenic enzyme sterol regulatory element-binding protein-1c (SREBP-1c) and its target genes in the liver. Luciferase reporter assay revealed that rhein suppressed the transcriptional activity of SREBP-1c through its upstream regulator, liver X receptor (LXR). This suggests that rhein exerts its effects by targeting LXR, which is also supported by its inability to reduce body weight in LXR knockout mice. Moreover, multiplex ELISA displayed a downregulated Th1 response after rhein treatment. Rhein shifted the Th1/Th2 responses by inhibiting T-box expressed in T-cells (T-bet) expression and enhancing GATA-binding protein-3 (GATA-3) expression through increased signal transducer and activator of transcription 6 (STAT6) phosphorylation. These data indicate that rhein ameliorated NAFLD and associated disorders through LXR-mediated negative energy balance, metabolic regulatory pathways, and immunomodulatory activities involved in hepatic steatosis. The combined effects of rhein to target hepatic metabolic and immune pathways may be beneficial for complex metabolic diseases such as NAFLD.

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Analysis of the Effect of Soluble Transferrin Receptor 1 (sTfR1) on Iron Metabolism in Mice.

Blood ◽

10.1182/blood.v106.11.3584.3584 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3584-3584 ◽

Cited By ~ 1

Author(s):

Jonathan M. Flanagan ◽

Hongfan Peng ◽

Pauline L. Lee ◽

Ernest Beutler

Keyword(s):

Iron Deficiency ◽

Iron Metabolism ◽

Transferrin Receptor ◽

Serum Iron ◽

Iron Absorption ◽

Biologically Active ◽

Soluble Transferrin Receptor ◽

Hepcidin Expression ◽

Transferrin Receptor 1 ◽

Hydrodynamic Transfection

Abstract Transferrin receptor 1 (TfR1) is a cell surface-expressed protein that mediates cellular uptake of iron. The TfR1 molecule may be shed from cells by proteolytic cleavage at Arg100 - Leu101, resulting in a cleaved form called soluble transferrin receptor 1 (sTfR1), which circulates in the blood as a 74 kDa monomer bound to transferrin. Measurement of soluble transferrin receptor has been widely used for the diagnosis of iron deficiency, but the levels of the receptor are also increased in patients with ineffective erythropoiesis, because the amount of circulating sTfR1 is directly proportional to the total amount of cell-associated TfR1. The key factors that stimulate increased sTfR1 levels are the integrated effects of reduced iron availability and increased erythropoietic stimulation. It is notable that both in iron deficiency and in diseases such as thalassemia, in which there is active ineffective erthropoiesis, iron absorption is increased This raises the question of whether sTfR1 is merely an intermediate in the degradation of the protein or whether it is a physiological regulator of iron absorption. To investigate this potential signaling function of sTfR1, a hydrodynamic gene transfer technique was established to express transfected plasmid constructs of human sTfR1 (hsTfR1, aa89–759) and murine sTfR1 (MsTfR1, 86–763) from the livers of C57Bl6 mice. To assess the effect that hsTfR1 and MsTfR1 might have on iron metabolism, iron absorption, serum iron and gene expression of hepcidin was measured in hydrodynamically transfected mice. The efficacy of the hydrodynamic technique was demonstrated by sustained expression of hsTfR1 in mice, at a level six fold higher than the normal level of hsTfR1 in humans (Fig. 1). Iron absorption was determined in transfected mice by measuring the retention of gavage fed 59Fe in a carrier iron solution, using a whole animal counting technique. Repeated experiments showed neither hsTfR1 nor MsTfR1 had any effect on the amount of iron absorbed. In agreement with these data, hepcidin levels were found by real time PCR to be unaltered in the same transfected mice. When serum iron levels were measured, expression of either hsTfR1 or MsTfR1 in mice resulted in significantly higher serum iron levels versus control mice (P=0.0141 and P=0.0192 respectively by t-test). We conclude that despite its attractiveness as a potential modifier of iron absorption, sTfR1 does not have any effect on hepcidin expression or iron absorption in mice. Mice transfected with hsTfR1 or MsTfR1 do have significantly higher serum iron levels, which may reflect an increased capability of these mice to retain transferrin in the serum. We have found that hydrodynamic transfection is a useful method to increase the levels of putative biologically active compounds in mice; this technique can be valuable in investigating the roles of serum or liver specific proteins in mice. Fig. 1 Sustained Expression of hsTfR1 in Mice Fig. 1. Sustained Expression of hsTfR1 in Mice

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Thermogenesis: Transferrin Receptor 1 Regulates Thermogenic Capacity and Cell Fate in Brown/Beige Adipocytes (Adv. Sci. 12/2020)

Advanced Science ◽

10.1002/advs.202070066 ◽

2020 ◽

Vol 7 (12) ◽

pp. 2070066

Author(s):

Jin Li ◽

Xiaohan Pan ◽

Guihua Pan ◽

Zijun Song ◽

Yao He ◽

...

Keyword(s):

Cell Fate ◽

Transferrin Receptor ◽

Transferrin Receptor 1 ◽

Beige Adipocytes ◽

Thermogenic Capacity

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Haploinsufficiency of Transferrin Receptor 1 Impairs Angiogenesis with Reduced Mitochondrial Complex I in Mice with Limb Ischemia

Scientific Reports ◽

10.1038/s41598-019-49983-4 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Keisuke Okuno ◽

Yoshiro Naito ◽

Seiki Yasumura ◽

Hisashi Sawada ◽

Masanori Asakura ◽

...

Keyword(s):

Iron Metabolism ◽

Transferrin Receptor ◽

Complex I ◽

Iron Transport ◽

Limb Ischemia ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

Intracellular Iron ◽

Transferrin Receptor 1 ◽

Adductor Muscles

Abstract Limb ischemia (LI) is a major consequence of peripheral artery disease (PAD) with a high mortality rate. Iron is an essential mineral to maintain physiological function of multiple organs. Intracellular iron transport is regulated by transferrin receptor 1 (TfR1). Although increase in serum ferritin levels has been reported in PAD patients, the mechanism of iron metabolism in LI is still unclear. The aim of this study is to investigate whether TfR1 deletion attenuates LI formation. To generate LI, the left femoral artery of 8–10 week-old C57BL6/J male mice was ligated. Adductor muscles were harvested at 28 days after surgery to investigate iron metabolism. The level of ferritin, intracellular iron storage protein, was higher in ischemic adductor muscles compared to non-ischemic adductor muscles. Level of intracellular iron transport protein, TfR1, was decreased in ischemic adductor muscles. LI was then generated in TfR1 heterozygous deleted mice (TfR1+/−) to examine whether TfR1 contributes to the pathophysiology of LI. Laser Doppler blood flowmetry revealed that blood flow recovery was attenuated in TfR1+/− mice compared to wild type (WT) littermates, along with decreased expression of ferritin and CD31 in ischemic adductor muscles. Since iron is used for energy production in mitochondria, we then assessed mitochondrial complexes in the ischemic adductor muscle. Of interest, expression of mitochondrial complex I, but not complexes II, III, and V in ischemic adductor muscles was significantly reduced in TfR1+/− mice compared to WT mice. Haploinsufficiency of TfR1 attenuated angiogenesis via reduction of mitochondrial complex I in LI in mice.

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